Photodynamic therapy (PDT) is a relatively new modality of cancer treatment and is currently being evaluated in clinical trials for treatment of superficial cancers of the bladder, lung, and other sites. PDT appears to be an effective therapy against various photon-resistant and drug-resistant tumor cell lines in vitro, presumably because its molecular target for cytotoxicity is not cellular DNA. It could play an expanded role in the treatment of resistant cancers if it could be applied to larger tumor volumes. One approach for accomplishing this aim is to illuminate solid tumors through interstitial fiber optical elements, by procedures analogous to some interstitial techniques of brachytherapy. A goal of our research is to irradiate tumor volumes with as uniform a photo-dose as possible to effect both uniform tumor cell cytotoxicity and uniform damage to tumor vasculature. The relative importance of these two mechanisms involved in PDT tumor response has not been determined, especially for larger tumors. We propose to continue the development of a computer photodosimetry code for rapidly estimating photon isodoses at various wave lengths across solid tumors. These computer generated photo-distributions will be verified by in situ measurements of photo-dose in Dunning R3327-AT and R3327-H tumors growing in Fischer x Copenhagen rats for 630, 690 and 750 nm laser light. Any discrepancies between measured and computer-calculated photo-doses will be investigated and serve to make appropriate adjustments to the computer code. We have previously shown that the addition of hypoxic cytotoxin chemotherapy to PDT can significantly potentiate PDT response and lead to increased tumor cures. This enhanced tumor response presumably results from increased drug cytotoxicity of cells which exist after treatment in PDT-induced hypoxic regions. Utilizing the mouse EMT-6 tumor model we propose to investigate interactions between PDT and hypoxic cytotoxin therapy both in vitro and in vivo. Selected studies are planned with the Dunning R3327-AT tumor model. The effectiveness of Misonidazole (MISO), Etanidazole (SR-2508),SRU-1069 and SR-4233 in adding to tumor response in vivo will be optimized. Preliminary data suggest that the administration of these drugs immediately after PDT produces maximum tumor growth delays, at least in the Dunning R3327-AT model, and that administration prior to PDT can result in protection against PDT, especially for cells at intermediate oxygen tensions.